JP2010512363A - Use of L-carnitine in the preparation of a medicament in the form of eye drops for the treatment of corneal diseases - Google Patents

Abstract

  Use of L-carnitine or a pharmaceutically acceptable salt thereof in the preparation of an ophthalmic physiological supplement or medicament in the form of eye drops for the treatment of corneal edema.

Description

  The present invention relates to a physiological nutritional supplement or medicament in the form of eye drops useful for the treatment of corneal diseases.

  In particular, the present invention provides a humidifier such as sodium hyaluronate; an antioxidant such as vitamin E; an inorganic and organic component such as zinc useful in the preparation of a physiological supplement or medicament for treating corneal edema. Relates to a physiological nutritional supplement or medicament in the form of eye drops for ophthalmic use, comprising L-carnitine, or a pharmaceutically acceptable salt thereof, as an active ingredient, in combination with manganese, sodium, potassium and taurine.

  The cornea is a transparent dome-shaped window that covers the front of the eye. A powerful refracting surface that provides 2/3 of the eye's focusing power. It provides a clear window to look through, like a crystal on the clock.

  The cornea is very sensitive and has more nerve endings than any other part of the body.

The adult cornea is only about 1/2 mm thick and is arranged in three main areas or layers:
Epithelium: A smooth surface that functions primarily to block the passage of foreign substances, such as dust or water, to other layers of the eye and cornea and absorbs oxygen and other necessary cellular nutrients contained in tears. provide. This layer is about 5 cells deep and is filled with thousands of small nerve endings, which makes the cornea very sensitive to the pain of rubbing and scratching.

  -Corneal parenchyma: Located behind the epithelium. The corneal stroma comprises about 90% of the cornea. The corneal stroma consists mainly of water and layered protein fibers (which give the cornea its strength, elasticity and form), and the cells that grow the corneal stroma. The unique shape, arrangement, and spacing of these protein fibers is essential to create transparency that conducts light in the cornea.

  -Endothelium: This single layer of cells is located between the corneal stroma and the aqueous humor. Since the corneal stroma is likely to absorb water, the primary task of the endothelium is to draw excess water from the corneal stroma. Without this sucking out function, the corneal stroma will swell with water, become wrinkled and eventually become opaque.

  Corneal edema or swelling occurs when the cornea can no longer keep itself clear and when liquid begins to accumulate in the cornea. The inner lining of the cornea serves to keep the cornea clear, and if this layer is damaged, symptoms of corneal edema can occur.

  Causes of corneal edema include: (a) damage to the inner layer of the cornea, eg Fuchs corneal endothelial degeneration; ophthalmic surgery, eg cataract surgery; eye trauma; acute glaucoma due to very high intraocular pressure; or (B) Neurotrophic keratopathy caused by: eg infection by herpes virus or mycobacterium leprae; traumatic injury, chirurgic injury, tumor, aneurysm or genetic factors Metabolic disorders due to diabetes or vitamin A deficiency; ophthalmology and laser surgery (chirurgy), contact lenses, iatrogenic disorders due to radiotherapy; abuse of local anesthesia, hypotonic eye drops, non-steroidal Toxic disorders due to chronic use of anti-inflammatory drugs, eye drop preservatives such as benzalkonium chloride; chemical or physical substances such as Exposure to acid, alkali, and attinic keratitis; blepharitis, springs keratoconjunctivitis, chronic papillary keratoconjunctivitis, chronic inflammation due to atopic keratoconjunctivitis; changes in position of the eyelid, eg thyroid Thyroideal ophthalmopathy, lid varus and lid valgus, febrile palsy.

  The treatment of corneal edema depends on its cause. Mild edema can be treated with hyperosmotic eye drops and ointments. This draws fluid from the cornea into the tears and helps clarify the cornea. More severe edema, particularly edema with blister formation, may require a corneal transplant to heal.

  The occurrence of corneal edema during the wearing of hydrogel contact lenses is well confirmed; however, the magnitude of swelling induced by the lenses cannot be fully explained in terms of response to hypoxia.

  Sodium hyaluronate is a very well known compound used to protect corneal epithelial cells, especially in patients with dry eye syndrome or Sjogren's syndrome. The action of sodium hyaluronate is not only due to the protective role of the mechanical type exerted on epithelial cells as a result of its viscoelasticity in the situation where tear production is reduced, but also the migration of corneal epithelial cells It is also due to the positive effect of its specific biological function on corneal epithelial cells by stimulating (Exp. Eye Res., 1991; 53: 753-758).

Taurine (or 2-aminoethanesulfonic acid) does not have the carboxyl group (COOH) characteristic of amino acids but has SO ₃ H, but is considered an amino acid. Taurine is present only in the animal territory, whereas plant foods do not have this amino acid.

  Vitamin E is the main antioxidant in the cell membrane and is found in the human body in four forms consisting of α-tocophenol, β-tocophenol, γ-tocophenol and δ-tocophenol. Of these, the α form is most frequently present in the retina and plasma and has the strongest antioxidant and free radical scavenging activities.

  The use of inorganic components is well known in the medical field and many of these are essential for tear film stability (Pescosolido 2000).

  The use of L-carnitine in the ophthalmic field is already known.

  Eur. J. Ophthalmol. 2003 Jan-Feb 13 (l): 80-5 reports that L-carnitine is useful in preventing retinal damage after ischemia-reperfusion.

  In J. Ocul, Pharmacol. 1994 Winter 10 (4): 643-51, free carnitine and acid-soluble acylcarnitine are present in various tissues of the rabbit eye and the eye has cells with muscle properties. Has been reported to play an important role in these tissues and may represent an important energy store after esterification.

  Res 1992; 18 (8): 355-365 describes the use of L-carnitine in the cardiological field.

  None of the patents or publications cited above describe or suggest the use of L-carnitine for the treatment of corneal edema.

  There is still a strong recognition in the medical field that there is a need for the availability of therapeutic or physiological nutritional supplements that are useful in the treatment of the above corneal diseases.

  In the present invention, a humidifier such as sodium hyaluronate; an antioxidant such as vitamin E; inorganic and organic components such as zinc, manganese, sodium, potassium and taurine; and optionally one or more ophthalmically acceptable Physiological nutritional supplement in the form of eye drops for ophthalmic use comprising L-carnitine, or a pharmaceutically acceptable salt thereof, as an active ingredient in combination with excipients and / or diluents Or it has been found that the medicament is useful for preparing a medicament or a physiological nutritional supplement for the treatment of corneal edema.

  What is meant by a pharmaceutically acceptable salt of L-carnitine is any salt of L-carnitine with an acid that does not produce toxic effects or side effects.

  These acids are well known to pharmacologists and pharmacists. Non-limiting examples of such salts include: chloride, bromide, orotate, aspartate, acid aspartate, acid citrate, magnesium citrate, phosphate, acid phosphorus Acid salt, fumarate and acid fumarate, magnesium fumarate, lactate, maleate and acid maleate, oxalate, acid oxalate, pamoate, acid pamoate, sulfate, Acid sulfate, glucose phosphate, tartrate and acid tartrate, glycerophosphate, mucinate, magnesium tartrate, 2-amino-ethanesulfonate, magnesium 2-amino-ethanesulfonate, methanesulfonic acid Salts, choline tartrate, trichloroacetate, and trifluoroacetate.

What is meant by a pharmaceutically acceptable salt of L-carnitine is also the FDA approved salt and Int. J. of Pharm. 33 (1986), 201-217 (incorporated herein by reference) Listed in the above. A further subject of the present invention is a physiological nutritional supplement or medicament in the form of eye drops for ophthalmic use, comprising as active ingredients:
-5-15% dose of L-carnitine; preferred dose is 10%;
-0.05-4% dose of taurine, the preferred dose is 2%;
-0.05-1.5% dose of sodium hyaluronate, the preferred dose is 0.2%;
-0.05-1.0% dose of vitamin E, the preferred dose is 0.2%;
-0.01-0.1 mg / L of manganese, the preferred dose is 0.051 mg / L;
-0.5-1.5 mg / mL dose of zinc, the preferred dose is 1.02 mg / mL;
A sodium dose of 5-5000 mg / L, the preferred dose is 30 mg / L;
A dose of potassium of -1-1000 mg / L, the preferred dose is 9 mg / L.

  Further subjects of the invention include (a) damage to the inner layer of the cornea due to Fuchs corneal endothelial degeneration; ophthalmic surgery, eg cataract surgery; eye trauma; acute glaucoma due to very high intraocular pressure; or (b) caused by: Neuroparalytic keratopathy: infection with, for example, herpesvirus or Hansen; lesions of the cranial nerve due to traumatic injury, surgical injury, tumor, aneurysm, or genetic factors; metabolic disorders due to diabetes or vitamin A deficiency Iatrogenic disorders due to ophthalmology and laser surgery, contact lenses, radiotherapy; abuse of local anesthesia, hypotonic ophthalmic drops, non-steroidal anti-inflammatory drugs, ophthalmic preservatives, such as chronic use of benzalkonium chloride Toxic disorder; exposure to chemical or physical substances such as smoke, acid, alkali, UV keratitis; blepharitis, spring catarrh, giant papillary horn Physiological nutrition for the prevention or treatment of corneal edema caused by conjunctivitis, chronic inflammation due to atopic keratoconjunctivitis; changes in the position of the eyelids such as thyroid eye disorders, eyelid varus and valgus hallux valgus, febrile bullosa Use of the eye drops of the present invention for the preparation of adjuvants or medicaments.

  The eye drops according to the invention comprise further antioxidants, such as vitamin C, vitamin A; borage oil; epithelial and anti-angiogenic agents; citicoline; humidifiers; inorganic components; regulators of cell osmolarity; An antiviral agent; an antifungal agent; and / or one or more alkanoyl L-carnitines selected from the group consisting of acetyl, propionyl, valeryl, isovaleryl, butyryl and isobutyryl L-carnitine, or pharmaceutically acceptable thereof It may further contain a salt.

  The following examples illustrate the invention.

  Fifteen patients with corneal edema (due to corneal cornea) were treated with the eye drops of the present invention for 1 month.

The following experiments were used to monitor patients before and after administration of eye drops of the present invention (weekly):
・ Electric corneal thickness measurement ・ Confocal microscopy ・ Contrast sensitivity

  The thickness of the cornea at the center and near the center was measured in microns using corneal thickness measurement. Five corneal layers were examined by confocal microscopy to evaluate the number of endothelial cells, their distribution by area (polymegathism) and distribution by horn (pleomorphism). Corneal parenchymal cells and epithelial cells were also examined using the same procedure. Finally, as a functional test, contrast sensitivity curves were plotted at various cycles every 0.5-12 degrees.

Results Analysis of the values obtained before and after administration of the eye drops of the present invention using corneal thickness measurements shows that the corneal thickness is reduced by about 25% in both the central and paracentral zone. After about 4-6 hours.

  Evaluation performed using confocal microscopy revealed clear signs that the keratocyte border was better determined and there was a significant reduction in edema. Similarly, this decrease was evident in epithelial cells.

  Functional testing corroborated morphological data with a significant increase in the value of the sensitivity curve, which restored physiological values.

  These therapeutic effects were confirmed / maintained during subsequent periodic medical device testing.

  L-carnitine is a known compound and its preparation is described in US Pat. No. 4,254,053.

  The physiological supplement or medicament according to the invention can be purchased with or without a medical prescription.

  The physiological nutritional supplements or medicaments according to the invention are composed of active ingredients well known to medical technicians and are already used in clinical practice, their pharmacotoxicological properties are known It is.

  Therefore, since they are currently on the market for a long time and are graded products suitable for human or animal administration, their acquisition is very easy.

The following are non-limiting examples of compositions according to the present invention.
Eye drops (approximately 1200 mOsm / L)
L-carnitine 10%
Taurine 2%
Sodium hyaluronate (sodium jaluronate) 0.2%
Vitamin E 0.2%
Zinc 1.02 mg / L
Manganese 0.051 mg / L
Sodium 30 mg / L
Potassium 9 mg / L
Sodium merthiolate 0.02 mg / mL
Demineralized water volume 5 mL / vial

Claims (6)

  L-carnitine as an active ingredient, or pharmaceutical thereof, in combination with humidifiers; antioxidants; inorganic and organic ingredients, and optionally one or more ophthalmologically acceptable excipients and / or diluents A physiological nutritional supplement or medicament in the form of eye drops for ophthalmic use comprising any pharmaceutically acceptable salt.   The eye drop according to claim 1, wherein the humidifier is sodium hyaluronate; the antioxidant is vitamin E; and the inorganic and organic components are manganese, sodium, potassium and taurine.   The ophthalmic solution according to claim 1, wherein the pharmaceutically acceptable salt of L-carnitine is selected from the group comprising: chloride, bromide, orotate, aspartate, acid aspartate, acid citrate. Acid salt, magnesium citrate, phosphate, acid phosphate, fumarate and acid fumarate, magnesium fumarate, lactate, maleate and acid maleate, oxalate, acid oxalic acid Salt, pamoate, acid pamoate, sulfate, acid sulfate, glucose phosphate, tartrate and tartrate, glycerophosphate, mucinate, magnesium tartrate, 2-amino-ethanesulfonate , Magnesium 2-amino-ethanesulfonate, methanesulfonate, choline tartrate, trichloroacetate, and trifluoroacetate. The eye drop according to claim 1, having the following composition:
-L-carnitine 10%
-Taurine 2%
-Sodium hyaluronate 0.2%
-Vitamin E 0.2%
−Zinc 1.02 mg / L
-Manganese 0.051 mg / L
-Sodium 30 mg / L
-Potassium 9 mg / L.   Use of the eye drop according to any one of claims 1 to 4 for the preparation of a physiological nutritional supplement or medicament for the prevention or treatment of corneal edema.   Antioxidants such as vitamin C, vitamin A; borage oil; epithelial and antiangiogenic agents; citicoline; humidifiers; inorganic components; regulators of cell osmolarity; antibiotics; antiviral agents; And / or further comprising one or more alkanoyl L-carnitines selected from the group consisting of acetyl, propionyl, valeryl, isovaleryl, butyryl and isobutyryl L-carnitine, or a pharmaceutically acceptable salt thereof. Use of description.